Clinical studies based on exploration of the mechanism(s) of action of antidepressants in patients and volunteers have been focused on three areas during the last year: 1. Algorithms for relating neurotransmitter measures provide new evidence of specificity of drug action and, as a corollary, new indices related to psychiatric diagnoses and/or clinical state. For instance, studies on the normetanephrine to MHPG ratio in cerebrospinal fluid (CSF) after treatment with idazoxan (IDZ) provide direct demonstrations of selective effects of putative alpha2) adrenergic antagonists in humans. 2. Evidence for clinical efficacy of IDZ in bipolar depression grows, providing a basis for new studies on related alterations of neuroendocrine and catecholamine function. IDZ (the alpha2 antagonist) produces sustained effects on the noradrenergic system in CSF, blood and urine and blocks the dose-dependent growth hormone release produced by the triazolobenzodiazepine, alprazolam, suggesting a physiologically relevant and testable functional interaction of the noradrenergic and GABAergic systems in humans. 3. Electroconvulsive therapy (ECT) in patients continues to be explored in depth. Despite increases of dopamine and serotonin metabolites in CSF, functional serotonergic responses are not altered by ECT. While ECT "normalizes" hyperresponsivity of the noradrenergic system, it does not affect CSF concentrations of the stress sensitive peptides CRH and ACTH. Thus, ECT reveals surprisingly discrete effects which can now be pursued in terms of their therapeutic and mechanistic relevance.